PROPOSAL SUMMARY (ABSTRACT) Distinguishing normal from pathological aging (such as Alzheimer?s Disease) is a major scientific goal. The projects in this application seek to utilize longitudinal design, neuroimaging techniques, and carefully selected candidate genes (single nucleotide polymorphisms; SNPs) to help uncover biological mechanisms in individual differences in brain and cognitive aging. This within-person approach is necessary to track how an individual (of any age) ages across time, and to selectively investigate the role of specific risk/protective factors while holding other variables constant (within-person design). Here we leverage data collected from R00 NIA award on 190 individuals aged 20-94 years to begin Wave 2 follow-up in Year 1 and Wave 3 in Year 4 of the proposed project. This will allow for three waves of data spanning 6.5 years in a five-year study, providing crucial information about individual differences in brain and cognitive aging. Specifically, this project aims to capitalize on the known biological effects of SNPs in the dopaminergic system (COMTval158 and DRD2 C/T) and in the regulation of neuroplasticity (BDNFval66met). Aging is accompanied by stark diminution to the dopamine neurons and those major brain regions they originate from and innervate. However, the brain is surprisingly plastic to these changes, and a major factor in regulating neuroplasticity is brain-derived growth factor. The first specific aim of the project is to investigate within-person change in persons with or without predisposition to reduced availability of dopamine in the synapses in frontal-parietal and fronto-striatal brain regions. We will examine change in ability to modulate this circuitry in functional MRI studies of cognitive challenge over the course of three follow-up points. We will further examine the brain structural changes (degradation of white matter connectivity, cortical thinning) that may mediate this change in neural function, as well as cognitive decline or preservation that results from these changes. The second specific aim will similarly examine within-person changes in modulation of brain activation to difficulty in persons with or without predisposition to reduced availability of neuroplasticity factors, particularly in limbic circuitry and the changes to brain structure that may mediate these functional changes and predict cognitive outcome. Our third aim utilizes an innovative neuroimaging technique, NODDI (neurite orientation dispersion and density imaging), to image with more specificity than previously possible the neurites which form synaptic units. We will introduce this in Wave 2, with follow-up in Wave 3 to measure change in dendrite/synaptic density, another marker of neuroplasticity. We will then further associate level and change in dendritic density in individuals based on genetic risk for reduced BDNF levels and at risk for Alzheimer?s Disease by examining neurite density in amyloid positive vs amyloid negative individuals, as well as those with APOEe4 positivity. Understanding biological mechanisms that guide individuals toward normal or pathological aging, like Alzheimer?s Disease, will help identify whom may respond best to future interventions to increase resilience to aging?s effects.